Somatostatin is an endogenous peptide that performs a variety of important functions within the body. Somatostatin is a highly flexible cyclic peptide with a very short biological half-life. Two known biologically active forms of somatostatin are a 14 mer (SRIF-14) and a 28mer N-terminal extended form (SRIF-28). Naturally-occurring somatostatin (also known as somatotropin release inhibiting factor, SRIF) was originally isolated from ovine hypothalamus.
Somatostatin, originally discovered to act as a classical endocrine hormone of the hypothalamic-pituitary system, has since been shown to act additionally as a paracrine and autocrine signaling factor on a wide variety of cell types. The numerous physiological processes currently recognized to be influenced by somatostatin include hormone and peptide factor secretion, neurotransmission, cell proliferation, smooth muscle contraction, nutrient absorption and inflammation. Hormones and peptides regulated by somatostatin include growth hormone (GH), thyroid-stimulating hormone (TSH), prolactin (PRL), insulin, and substance P (SP).
Somatostatin affects the function of many important biological systems such as the endocrine, gastrointestinal, vascular, and immune systems along with the central and peripheral nervous systems. In the endocrine system, somatostatin plays an important role in controlling growth hormone, insulin and glucagon secretion (Koerker et al., Science 1974, 184, 482–484). The effects of somatostatin on the gastrointestinal and vascular biological systems have led to clinical applications for somatostatin therapeutics in both of these areas. In the central nervous system (CNS), somatostatin appears to be an important regulator of cognitive functions (Schettini, Pharmacological Research 1991, 23, 203–215) and, in specific areas of the brain, appears to act as a neurotransmitter or as a neuromodulator regulating the release of neurotransmitters such as acetylcholine (Gray et al., J. of Neuroscience 1990, 10, 2687–2698) and dopamine (Thal et al., Brain Research 1986, 372, 205–209). In the peripheral nervous system (PNS), somatostatin is present in catecholamine containing fibers and in sensory terminals together with substance P (Green et al., Neuroscience 1992, 50, 745–749) and acts to inhibit their release and mediated effects.
Somatostatin is expressed in diverse cell types of the immune and hematopoietic systems (Hofland et al., Ann. Medicine 1999, 31 Suppl. 2, 23–27) and has been shown to has been demonstrated that somatostatin is important as an endogenous inhibitor of cell proliferation in various normal and neoplastic tissues (Reubi et al., Trends in Pharmacological Sciences 1995, 16, 110–115).
The biological effects of somatostatin are mediated through five somatostatin G-protein receptor subtypes, SSTR1-5 (Reisine et al., Endocrine Reviews 1995, 16, 427–442), that are highly conserved across different species and can be grouped into two families SSTR 2, 3, and 5, and SSTR 1 and 4. All five receptors are heterogeneously distributed and pharmacologically distinct. Studies utilizing subtype selective somatostatin receptor agonists have provided evidence that somatostatin subtype 2 receptors (SSTR2) mediate the inhibition of growth hormone release from the anterior pituitary and of glucagon release from the pancreas; whereas SSTR5 receptors mediate inhibition of insulin release.
Like somatostatin itself, somatostatin receptors have been localized to a wide variety of tissues and cell types including those belonging to the CNS, PNS, endocrine, gastrointestinal, vascular, and immune systems. A high incidence of somatostatin receptors has also been demonstrated in a variety of human tumors. Neuroendocrine tumors are one class of tumors that exhibit a high density of functionally active somatostatin receptors. Functionally active neuroendocrine tumors present with clinical symptoms such as gastrinoma and glucagonoma syndrome due to excessive hormone release from the tumor cell. Such symptoms may be treated through somatostatin receptor activation.
Another group of tumors recognized as having somatostatin receptors originates in the CNS, which includes both the brain and the spinal cord. While most brain tumors contain somatostatin receptors, their receptor content often varies depending on tumor type. Generally, tumors of glial or meningeal origin, including medulloblastomas, oligodendrogliomas, and differentiated astrocytomas, display somatostatin receptors.
Additional tumors characterized as displaying somatostatin receptors include kidney, breast, and lymphomas, endometrial (Mishima et al., American Journal of Obstetrics and Gynecology 1999, 181, 583–590), ovarian (Halmos et al., Journal of Clinical Endocrinology and Metabolism 2000, 85, 3509–3512), small cell lung, and prostate (Reubi et al., Trends in Pharmacological Sciences, 1995, 16, 110–115).
It has been reported that somatostatin may act directly on cells, e.g., inducing cell death by apoptosis (Srikant, Biochemical and Biophysical Research Communications 1995, 209, 400–406). Alternatively, somatostatin may influence tumor growth by indirect mechanisms including effects on growth factor levels that correlate with tumor growth, e.g., IGF-1, or by blocking angiogenesis via inhibiting the proliferation of vascular endothelial cells (Watson et al., British Journal of Cancer 2001, 85, 266–272).
Along with somatostatin (SRIF-14) itself, several somatostatin peptide analogs are currently available for various clinical uses. Such uses have been established for cyclic octapeptide therapeutic analogues, including for example, octreotide (Bauer et al., Life Sciences 1982, 31,1133), lanreotide (Guisti et al., European Journal of Clinical Investigation 1997, 27, 277), and vapreotide (Liebow et al., Proceedings of the National Academy of Sciences 1989, 86, 2003). These compounds were originally characterized by their binding effects to prepared rat brain membrane and their effects on endocrine parameters in animals. Structure activity studies on somatostatin peptide analogs have demonstrated that the amino acid side chains from the Phe-Trp-Lys tripeptide subsequence of somatostatin play a key role in receptor binding affinity. The three dimensional structure of octreotide has been determined by x-ray crystallographic studies (see Pohl et al., Acta Crystallographica 1995, D51, 48–49). Nuclear magnetic resonance (NMR) structure studies have been performed on other somatostatin peptide analogs (Kessler et al., Journal of the American Chemical Society 1983, 105, 6944–6952). These studies indicate that the three dimensional geometry of the amino acid side chains based on the somatostatin Phe-Trp-Lys tripeptide subsequence is defined by a β-turn structure.
Many of the therapeutic properties of somatostatin and somatostatin peptide analogs discussed above can be correlated with the functional activation of the SSTR2 somatostatin receptor subtype as characterized using in vitro cellular constructs which have been transfected with the five individual cloned human somatostatin receptor subtypes.
Current somatostatin peptide therapeutics suffer from numerous drawbacks. Major drawbacks include lack of oral activity, relatively short plasma half life, and poor penetration of the blood retinal barrier (BRB) and of the blood brain barrier (BBB) to access the central nervous system. As a result, somatostatin peptide analog therapeutics are administered to patients in an invasive fashion via injection of an aqueous drug solution up to four times daily, generally by subcutaneous route or by a long acting depot polymer based formulation that is injected every 3–4 weeks with supplemental injections of aqueous drug as needed.
Thus, treatments using currently available somatostatin peptide-based therapeutics lack ease of administration and are not highly selective to specific somatostatin receptor subtypes. Therefore, there exists an unfulfilled need for longer acting, therapeutic non-peptide somatostatin receptor ligands that have greater receptor subtype selectivity, can readily penetrate the BBB and/or the BRB, and can be delivered using non-invasive pharmaceutical methods including oral administration. It is the object of this invention to provide non-peptide somatostatin receptor ligands that meet the unfulfilled needs detailed above.